Vol 16, No 4 (2018)

Vegetative polysaccharides: new target and direction of clinical use
Chernykh I.V., Shchulkin A.V., Popova N.M., Kirichenko E.E., Yakusheva E.N.

P-glycoprotein (Pgp, ABCB1-protein) is a membrane efflux protein transporter located in hepatocytes, enterocytes, epithelial cells of the proximal renal tubules, histogematic barriers, and also in tumor cells, which releases the substrates from cells and plays an important role in pharmacokinetics of drugs. Inhibition of Pgp functional activity is promising for increasing the effectiveness of drug treatment of oncological diseases and pharmacoresistant epilepsy, but today no synthetic inhibitor of the transporter can be used in clinical practice because of side effects development. The aim of this review is to prove the relevance to use polysaccharides of plant origin, their derivatives and chemical modifications as effective, safe and cost-effective inhibitors of the transporter protein. The article describes the chemical structure of Pgp substrates and inhibitors, the ability to predict the drugs belonging to the transporter protein substrates or inhibitors. Some results of investigations of the belonging of oligo- and polysaccharides to Pgp substrates and inhibitors are presented. They are premises for carrying out appropriate experiments for polysaccharides of plant origin both in vitro and in vivo.

Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(4):5-9
Relationship of clinical efficacy of glucose lowering agents, gut microbiota, diet, and patient’s genotype in diabetes mellitus type 2
Urakov A.L., Gurevich K.G., Sorokina I.A., Lovtsova L.V., Zanozina O.V., Barsuk A.L.

The review is devoted to revealing the connection between the intestinal microflora, diet and the effectiveness of glucose – lowering therapy in patients with type 2 diabetes. Potential targets and the effects of oral and injectable hypoglycemic agents on microbiota in this category of patients are considered. The work reflects modern views on hypoglycemic drugs from the standpoint of the science of metabolomics within the framework of personalized medicine.

Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(4):11-18
Network meta-analysis: a comparison of effectiveness and safety of partial agonists of nicotinic acetylcholine receptors varenicline and cytisine for smoking cessation
Radchenko E.V., Sykhovskaya O.A., Galankin T.L., Kolbin A.S., Smirnova M.A.

Background. Partial agonists of α4b2 nicotinic acetylcholine receptors are the most effective treatment strategy for tobacco smoking cessation. They are able to alleviate withdrawal symptoms and to reduce smoking satisfaction.

The aim of this study was to review the efficacy and safety of nicotinic receptor partial agonists varenicline and cytisine, for smoking cessation.

Methods. A search for randomized controlled trials was done using the terms (“cytisine”, “tabex”, “varenicline” or 'partial agonists of nicotinic receptors’) in MEDLINE, EMBASE, eLibrary in May 2018. Types of participants, the doses and duration of the treatments, efficacy and safety parameters, quality of randomization and blinding procedures were evaluated. Bayesian network meta-analysis was performed.

Results. Cytisine overcame placebo in the 12, 24 and 52 weeks of therapy with the following odds ratios (ORs) for abstinence: 3.3 (95% CrI 1.8–5.8), 3.9 (2.4–6.7), 3.8 (CrI 1.3–11,9) accordingly. Varenicline in 2 mg/day dose overcame placebo in the 12, 24 and 52 weeks of therapy with the ORs: 4.0 (3.3–4.7), 3.1 (2.5–3.7), 2.9 (2.2–4.1) accor dingly. Varenicline in 1 mg/day dose overcame placebo in 12 and 52 weeks of therapy, the ORs were 3.0 (2.0–4.7) and 2.3 (1.3–4.4) accordingly. Varenicline in 0.5 mg/day dose overcame placebo in 12 weeks of therapy only with the OR 2.4 (1.3–4.4). Cytisine and varenicline 2 mg/day were associated with more gastrointestinal disturbances than placebo with the ORs 6.2 (2.1–22.8) and 2.4 (2.0–2.8) accordingly. Cytisine and varenicline 2 mg/day were associated with more psychiatric problems than placebo with ORs 5.2 (1.9–15.1) and 1.6 (1.3–1.9) accordingly. There was no difference in serious adverse events between the investigated drugs and placebo: OR for cytisine was 2.4 (0.8–6.8), varenicline 0.5 mg/day – 2.0 (0.5–6.6), varenicline 1.0 mg/day – 1.0 (0.3–2.7), varenicline 2 mg/day – 1.0 (0.7–1.4).

Conclusion. Cytisine was proved to be as effective and safe aid for smoking cessation as varenicline.

Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(4):19-32
Prospects for the use of new generation of anti-tuberculosis drugs in treatment of drug-resistant tuberculosis (experimental and clinical study)
Pavlova M.V., Vinogradova T.I., Zabolotnykh N.V., Ershova E.S., Sapozhnikova N.V., Chernokhaeva I.V., Archakova L.I., Vitovskaya M.L., Dogonadze M.Y., Starshinova A.A., Grishko A.N., Yablonsky P.K.

The aim of this work was an experimental and clinical study of increasing of the efficiency of therapy of respiratory tuberculosis with drug resistant pathogen by including a combination of anti-tuberculosis drugs of new generation – Bedaquiline (Bq) and Thioureidoiminomethylpyridinium perchlorate (perchlozone, Tpp) into treatment regimens. The presented results were obtained: in the experiment on a model of tuberculosis infection in 103 male C57black / 6 mice, reproduced by inserting into the lateral vein of the tail of a suspense of clinical strains of Mycobacterium tuberculosis with multi-drug resistance and with various combinations of mutations in the genes; in the clinic – on the basis of examination and treatment of 148 patients with multidrug-resistant respiratory tuberculosis. It is shown that the application of the therapy schemes for multiple and broad drug resistant tuberculosis, containing Bq and Tpp in combination with drugs, selected taking into account the drug sensitivity of mycobacteria, allows to significantly reduce the periods of relief of symptoms of intoxication, regression of inflammatory changes, abacillation and achieving positive X-ray dynamics. Undesirable phenomena against the background of combined prescription of new generation drugs, as a rule, corresponded to light and moderate severity, and in frequency of development and expression did not differ from control groups of observation.

Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(4):33-40
The effectiveness of the antioxidant aminothiol series on the model of multiple sclerosis
Okunevich I.V.

In the experiments on an reproducible adequate model of multiple sclerosis – experimental autoimmune encephalomyelitis as a result of the creation of pathological condition by immunization of guinea pigs with an encephalitogenic mixture in the complete Freund’s adjuvant, a pronounced inhibitory effect of the Ttriafen preparation was shown. The synthesized preparation of Ttriafen with antihypoxic and antioxidant properties on the experimental autoimmune encephalomyelitis model was used for chronic administration for 35 days, orally at a dose of 50 mg/kg. This drug is known to be free radical scavenger. A number of immunological indices and the clinical picture of neurological complications and the severity of central nervous system damage in experimental guinea pigs were studied. The circulating antibody production was estimated using the complement fixation test. In the peripheral blood, the content of lipid peroxidation products and antioxidant defense enzymes was evaluated. In another series of experiments, the lethality of animals after inoculation of the encephalitogenic mixture in Freund’s complete adjuvant and the protective effect of Triafen’s preparation were reproduced. In the present study, it has been established that the synthetic preparation of the aminothiol Triafen series on the experimental model of multiple sclerosis shows a neuroprotective and immunomodulating property, and increases the resistance to the intensification of LPO processes.

Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(4):41-44
Orexin A content in brain structures correlates with behavioral patterns in stressed rats
Khokhlov P.P., Tissen I.Y., Lebedev A.A., Bychkov E.R., Shabanov P.D.

The aim of this investigation was to reveal correlations between some behavioral patterns and orexin concentrations in the brain structures in rats after an acute psychoemotional stress. A group of rats was placed into a chamber with a tiger python for 25 mi nutes and then as a treatment these rats received orexin A or its antagonist SB-408124 administered intranasally for 7 days. Then the quantitive indexes of behavioral patterns in open field and elevated plus maze were registered. The orexin A level was investigated in the brain structures (amygdala, hippocampus, hypothalamus) of such rats by means of high-sensitive ELISA. The correlations were assessed with Spearman’s rank correlation test. As a result, a correlation between orexin A content in the amygdala and hypothalamus and a number of ambulations (line crossings) characterizing motor activity in open field test has been revealed. Therefore, the level of orexin A in the amygdala and hypothalamus demonstrates a direct and reverse link with locomotor activity of rats respectively. Also a correlation between orexin A level in the hippocampus and amygdala and the time of staying in the dark alleys of the elevated plus maze has been revealed. So, the content of orexin A in the hippocampus and amygdala reflects anxiety level of a rat. It is concluded there is a positive correlation between the orexin A content in the limbic structures of the brain and emotional behavior of rats.

Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(4):45-48
Synthetic analogs of vitamin D3 in therapy of psoriasis
Petrova I.V., Radzhabov R.M., Abdulov A.R., Manatov M.G., Glushakov R.I., Proshin S.N.

Psoriasis is one of the most common skin diseases and occurs in 1-2% of the population of developed countries. The problem of pathogenetic treatment of psoriasis remains relevant despite the annual appearance of new drugs. The anti-keratinizing effect is particularly important in the treatment of psoriasis. The effect is based on suppression of the proliferation of epidermal keratinocytes, normalization of the differentiation of the nonkeratinizing epithelium and the decrease in the adhesion of horny cells. The last decade is characterized by a deepening of ideas about the biological properties and mechanism of action of vitamin D3. However the vitamin D3 does itself not have therapeutic activity. In this connection the use of synthetic analogues of vitamin D3 which have therapeutic activity is particular of importance.

The aim. To evaluate the effectiveness of vitamin D3synthetic analogs for the treatment of psoriasis.

Methods. It was retrospective analysis of multicentric studies by a double-blind, randomized method of the effectiveness of vitamin D3 analogs for the treatment of psoriasis in Russia and foreign clinics. The PASI index in assessing the clinical manifestations of psoriasis.

Rеsults and discussion. The study of the clinical efficacy of oral forms of the vitamin indicates a positive therapeutic effect in 70-90% of patients but this requires an average of 2.8 months. Therefore for the treatment of psoriasis more widely used synthetic analogue of vitamin D3 – calcipotriol (MS-903), developed exclusively for topical application. Calcipotriol gives minimal side effects and has an intense antipsoriatic effect. The mechanism of action of calcipotriol is based on interaction with specific receptors on keratinocytes which causes inhibition of proliferation, accelerates the morphological differentiation of psoriatic cells, inhibits the activity of interleukin-1 and reduces interleukin-2 production, i.e. has an effect on the pathogenetic mechanisms of psoriasis.

Conclusion. Vitamin D3 analogues are effective antipsoriatic drugs that can be used both as monotherapy and in the complex treatment of patients with severe psoriasis.

Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(4):49-54
Sensitivity to placebo therapy in patients with alcohol dependence in postwithdrawal period
Vostrikov V.V., Shabanov P.D.

40 patients with alcohol dependence in post-abstinent period was used to study the psychological peculiarities of emotional-motivational sphere during the course of placebo therapy. The placebo-reactor was 62.5%, placebo preaction – 15%, placebo-negative reactors of 22.5%. There are significant differences in the compared groups of patients. After a course of placebo-therapy all patients showed positive changes in emotional state, most pronounced in placebo-directoru. The least pronounced changes in the placebo group-negative patients (but to lessen the desire for alcohol most pronounced). The conclusion about the need for a differentiated approach to the treatment of alcohol withdrawal syndrome and postdetoxification state.

Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(4):55-60
Neurodystrophic component of pathogenesis of the acute postoperative pancreatitis and its prevention by epidural anesthesia
Zabrodin O.N., Strashnov V.I.

The data on the etiology and pathogenesis of acute postoperative pancreatitis (APP) are analyzed. It is noted that in its pathogenesis, currently, the main attention is paid to the factors of aggression in the pancreas: the activation of proteolytic enzymes and autocatalytic reactions leading to damage of the acinous cells, microcirculation disturbance, and enhancement of free radical oxidation. This determines the prevention and treatment of acute postoperative pancreatitis with the use the inhibition of protease and exocrine secretion of pancreas, antioxidants and cytostatics. Biochemical mechanisms of resistance of the pancreas tissue to damage are given much less attention. The authors substantiate the proposition that organ tissue resistance, besides adequate microcirculation and oxygenation, is determined by the mechanisms of nerve tropism mediated through the sympathetic nervous system. Experimental and clinical data are presented that irritation of the reflexogenic pyloroduodenal zone, in particular during operations in conditions of inadequate anesthesia, leads to hyper activation of the sympathetic nervous system, increased release of the noradrenaline, subsequent depletion of its content in the pancreas tissues. Therefore adrenergic support of trophic (energy and plastic processes) in the pancreas is disrupted, contributing to the development of postoperative complications, including acute postoperative pancreatitis. Taking into account that epidural anesthesia performs afferent and efferent, including sympathetic, blockades; the substantiations are given for use epidural anesthesia for acute postoperative pancreatitis prevention in abdominal operations in combination with the components of general anesthesia.

Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(4):61-66
“Сhinese date”, “Lungberry” - elitist plant drug of the ancientest asiatic traditional medicines (the second report)
Barnaulov O.D.

The lot of using Ziziphus jujube in traditional medicines phytotherapy, prescriptions species for treating patients with lung tuberculosis and other lung-bronchial diseases is observed in this article. The high effectiveness of such treating was confirmed by my own clinical experience. Fruits and leaves Zizyphus jujubа in polycomponent plant compositions protected the liver from hepatotoxic action of aggressive drugs. Some information about chemical composition Ziziphus jujube is given. This information permit only limited opportunity to base and gave prognosis of galenic forms activity. Correction carbohydrate and lipid metabolism by Zizyphus jujubа drugs may be used for treating patients with diabetes, arteries atheromatosic injuries. Immunocorrective properties this medical plant concluded in polycomponent compositions may be used for treating patients with sclerosis dissiminata. Effectiveness such compositions confirmed personally by results of phytotherapy more 500 patients with sclerosis dissiminata.

Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(4):67-74
Analysis of efficiency of integrated preparations of medicinal plants in regulation of decadaptatic disorders in a practically healthy person
Sambukova T.V., Yatmanov A.N., Yusupov V.V., Shabanov P.D.

Relevance. In recent years, the popularity of phytotherapy, despite the great success in the development of chemical medicines, is increasing. Interest in natural healing substances and preparations created on their basis is increased due to both the unique properties of phytopreparations and rapidly developing research technologies in biology, medicine and the production of medicines.

Methodology. The analysis of the publications studying medicinal plant preparations in the VINITI databases, in the electronic resource of the Russian National Library, search engines Yandex, Google, Cyberleninka and Scholar Google for 2000-2014 was carried out.

Results. Studies conducted with human participation are few and account for 15% for drugs with names and 25% for drugs presented as original studies without a name from the total number of complex drugs studied. The spectrum of the revealed pharmacological effects was extremely wide, and the revealed effects, as a rule, were multicomponent. The greatest number of publications is devoted to the results of the study of Noofit. The drug was studied primarily in experimental studies.

Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(4):75-79

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